Sterile drug products provide a number of benefits, both medically and economically. The medical ramifications requiring sterile drug preparations are clear in that the use of non-sterile preparations may subject the patient to an unnecessary risk of secondary infection from the contaminating microbe, a microbe that is at least resistant to the drugs of the preparation. Furthermore, even if the contaminant is innocuous, the growth can result in loss of active drug products per se with possible concomitant generation of toxic by-products. Economically, contaminated drug products have a shortened shelf life, which requires increased production expenses to replace product on a more frequent basis.
Methods are needed for the preparation of sterile products for patient use. However, the problem associated with many sterilization procedures is that the process often results in unfavorable changes in the drug profile. These changes in the drug profile can range from loss of activity, to increased degradation products being created, or possible alteration of the chemical or physical characteristics of the compound sterilized. These problems are especially pronounced when glucocorticosteroids are sterilized.
Sterilization of materials relies on the input of sufficient energy to be lethal to any potential microbial contamination. Numerous methods including heat, radiation, and chemicals have been proposed for the sterilization of glucocorticosteroids. However, to date these methods often result in the excess production of degradants or a loss of activity for the glucocorticosteroid being sterilized. Additionally, as in the case of glucocorticosteroid suspension formulations for metered dose inhalation, the commonly used sterilization procedures often results in unacceptable changes to drug particle size.
Chemical sterilization, for the most part, has been based on exposure to toxic compounds, for example, ethylene oxide. However, when used to sterilize glucocorticosteroids, ethylene oxide has been found to leave residual amounts of ethylene oxide in the drug preparation. Ethylene oxide is toxic and the residual levels are often above the pharmaceutically acceptable limits as set by most regulatory agencies.
Irradiation based sterilization is known and has been recommended for glucocorticosteroids (see Illum and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However, significant degradation has been reported when irradiation has been used to sterilize micronized glucocorticosteroids.
WO 00/25746 (Chiesi) discloses a process for preparing a suspension of a glucocorticosteroid. In a first step an aqueous carrier is mixed in a turboemulsifier and sterilized by heat treatment or filtration. In a second step a micronized active ingredient (e.g. a glucocorticosteroid), pre-sterilized by gamma irradiation, is added to the aqueous carrier.
WO 03/086347 (Chiesi) describes some of the disadvantages of WO 00/25746 and discloses an improvement in the process whereby the active ingredient is introduced into a turboemulsifier as a powder by exploiting the vacuum in the turboemulsifier. Again the active ingredient is sterilized prior to dispersion in the aqueous carrier.
Neither of these documents disclose the sterilisation by heating of an aqueous suspension of a glucocorticosteroid and hence the problem of particle size growth during the heating and subsequent cooling steps is not addressed.
U.S. Pat. No. 3,962,430 (O'Neill) discloses a method for the production of sterile isotonic solutions of medicinal agents. The method comprises adding the medicinal agent to a saturated solution of sodium chloride in water at 100° C. The drug/saturated sodium chloride solution is then heated to 100-130° C. This method, which purportedly is based on the theory that the sodium chloride ions tie up free water thereby preventing hydrolytic degradation, is not suitable for suspensions of fine particles of glucocorticosteroids intended for inhalation, as the procedure produces unfavorable changes in the size of the particles. Additionally, the procedure can result in bridge formation between drug particles producing large aggregates, which do not break up on administration.
In order to address the problem of particle growth, U.S. Pat. No. 6,392,036 (Karlsson) discloses a method for the dry heat sterilization of powdered glucocorticosteroids that can then be used for drug formulations. However, this method results in unacceptable levels of heat-degradation products.
WO 2004/078102 (Dompe) discloses a method for sterilizing an aqueous suspension of a glucocorticosteroid consisting of the glucocorticosteroid and water only. Minimal detail is provided of the sterilisation apparatus.